The oral bioavailability of ubiquinol recently has been reported to be greater than that of ubiquinone in healthy adults. The basis for this influence of redox state of coenzyme Q (CoQ) on bioavailability has been investigated using the coupled in vitro digestion/Caco-2 cell model. Solubilized ubiquinol and ubiquinone were added to yogurt and subjected to simulated gastric and small intestinal digestion. Partitioning of CoQ in mixed micelles during small intestinal digestion was significantly greater during digestion of yogurt enriched with ubiquinol. Similarly, apical uptake from mixed micelles and transepithelial transport of CoQ by Caco-2 cells were significantly greater after digestion of the ubiquinol-rich yogurt compared to digested ubiquinone-rich yogurt. Reduction of cellular GSH significantly decreased cell uptake and basolateral secretion of both ubiquinol and ubiquinone, although the adverse impact was much greater for ubiquinol. These data suggest that the enhanced bioaccessibility and bioavailability of ubiquinol compared to ubiquinone results from reduced coenzyme being more efficiently incorporated into mixed micelles during digestion and its greater uptake and basolateral secretion in a glutathione-dependent mechanism.